Hypoglycaemia revealing heterozygous insulin receptor mutations.
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ABSTRACT:
SUBMITTER: Preumont V
PROVIDER: S-EPMC5643506 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice. METHODS AND FINDINGS:We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth. CONCLUSIONS:HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.
| S-EPMC1845156 | biostudies-literature
Project description:ObjectivePrediabetic states are associated with accelerated atherosclerosis, but the availability of mouse models to study connections between these diseases has been limited. The aim of this study was to test the selective role of impaired insulin receptor/insulin receptor substrate-1 signaling on atherogenesis.Methods and resultsTo address the effects of impaired insulin signaling associated with hyperinsulinemia on atherosclerosis in the absence of obesity and hyperglycemia, we generated insulin receptor (Insr)/insulin receptor substrate-1 (Insr1) double heterozygous apolipoprotein (Apoe)-knockout mice (Insr(+/-)Irs1(+/-)Apoe(-/-)) mice. Insr(+/-)Irs1(+/-)Apoe(-/-) mice fed a Western diet for 15 weeks showed elevated levels of fasting insulin compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. There were no significant differences in glucose, triglyceride, HDL, VLDL, cholesterol levels or free fatty acid in the plasma of Insr(+/-)Irs1(+/-)Apoe(-/-) and Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Atherosclerotic lesions were increased in male (brachiocephalic artery) and female (aortic tree) Insr(+/-)Irs1(+/-)Apoe(-/-) compared to Insr(+/+)Irs1(+/+)Apoe(-/-) mice. Bone marrow transfer experiments demonstrated that nonhematopoietic cells have to be Insr(+/-)Irs1(+/-) to accelerate atherosclerosis. Impaired insulin signaling resulted in decreased levels of vascular phospho-eNOS, attenuated endothelium-dependent vasorelaxation and elevated VCAM-1 expression in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice. In addition, phospho-ERK and vascular smooth muscle cell proliferation were significantly elevated in aortas of Insr(+/-)Irs1(+/-)Apoe(-/-) mice.ConclusionsThese results demonstrate that defective insulin signaling is involved in accelerated atherosclerosis in Insr(+/-)Irs1(+/-)Apoe(-/-) mice by promoting vascular dysfunction and inflammation.
| S-EPMC3676303 | biostudies-literature
Project description:AIMS:A prospective meta-analysis of phase 3 trials showed lower rates of nocturnal hypoglycaemia with insulin degludec vs. insulin glargine. We investigated the consistency of the results across different definitions of hypoglycaemia. METHODS:This post-hoc, patient-level meta-analysis included six randomized, controlled, 26- or 52-week phase 3a trials in insulin-naïve participants with Type 2 diabetes mellitus (Type 2 diabetesinsulin naïve ), participants with Type 2 diabetes mellitus using basal-bolus therapy (Type 2 diabetesBB ) and those with Type 1 diabetes mellitus. We used three definitions of hypoglycaemia and different timescales for the nocturnal period. Rates were analysed for the entire core trial period, the 'maintenance period' only, and the extension trial set population. Analyses utilized a negative binomial regression model. RESULTS:In Type 2 diabetesinsulin naïve participants, risk of nocturnal hypoglycaemia was significantly lower with insulin degludec vs. insulin glargine for all hypoglycaemia definitions and trial periods. Risk was also lower for the timescale 21.59-05.59, but not 00.01-07.59. For Type 2 diabetesBB , nocturnal hypoglycaemia rates were lower with insulin degludec vs. insulin glargine across all definitions, timescales and trial periods, with one exception. For individuals with Type 1 diabetes mellitus, nocturnal hypoglycaemia risk was significantly lower with insulin degludec during the maintenance period for the original definition (plasma glucose < 3.1 mmol/l, timescale 00.01-05.59) and in the extension trial set population for all hypoglycaemia definitions except for the nocturnal timescale 00.01-07.59. CONCLUSIONS:Compared with insulin glargine, insulin degludec is associated with lower rates of nocturnal hypoglycaemia in people with Type 2 diabetes mellitus, and similar or lower rates in Type 1 diabetes mellitus, across different definitions.
| S-EPMC5064738 | biostudies-literature
Project description:AIMS:To re-analyse, using a series of alternative hypoglycaemia definitions, the data from 2 trials, DUAL I and V, in which the once-daily, fixed ratio combination of insulin degludec/liraglutide (IDegLira) was compared with basal insulin therapy. MATERIAL AND METHODS:Post hoc analyses of the DUAL I (patients uncontrolled on oral antidiabetic drugs) and DUAL V (patients uncontrolled on insulin glargine (IGlar) U100) trials were carried out using different definitions of hypoglycaemia and according to whether treatments were administered in the morning or afternoon. Rates of hypoglycaemia for the definitions of confirmed and American Diabetes Association (ADA)-documented symptomatic hypoglycaemia were compared according to age, gender and body mass index (BMI). RESULTS:Although hypoglycaemia rates differed according to the alternative hypoglycaemia definitions, rates were consistently lower with IDegLira vs insulin degludec (IDeg) and IGlar U100. Despite glycated haemoglobin concentrations being lower with IDegLira at end of treatment, confirmed and nocturnal-confirmed hypoglycaemia rates were lower for IDegLira vs IDeg and IGlar U100, irrespective of dosing time. The definitions of confirmed and ADA-documented symptomatic hypoglycaemia did not have a significant effect on the treatment difference between IDegLira and IDeg, liraglutide or IGlar U100 when further assessed by baseline age, gender and BMI. CONCLUSIONS:Treatment with IDegLira, vs IDeg and IGlar U100, resulted in lower rates of hypoglycaemia regardless of dosing time and definition of hypoglycaemia used. The choice of hypoglycaemia definition did not influence the results of analyses when stratified by age, sex and BMI.
| S-EPMC5655847 | biostudies-literature
Project description:Injectable insulin is an extensively used medication with potential life-threatening hypoglycaemic events. Here we report on insulin-conjugated silver sulfide quantum dots coated with a chitosan/glucose polymer to produce a responsive oral insulin nanoformulation. This formulation is pH responsive, is insoluble in acidic environments and shows increased absorption in human duodenum explants and Caenorhabditis elegans at neutral pH. The formulation is sensitive to glucosidase enzymes to trigger insulin release. It is found that the formulation distributes to the liver in mice and rats after oral administration and promotes a dose-dependent reduction in blood glucose without promoting hypoglycaemia or weight gain in diabetic rodents. Non-diabetic baboons also show a dose-dependent reduction in blood glucose. No biochemical or haematological toxicity or adverse events were observed in mice, rats and non-human primates. The formulation demonstrates the potential to orally control blood glucose without hypoglycaemic episodes.
| S-EPMC11026164 | biostudies-literature
Project description:Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations. To investigate the impact of genetic insulin resistance on transcriptional regulation in iPSCs, we analyzed global gene expression using microarrays in both fibroblasts and iPSCs.
2016-03-04 | GSE78891 | GEO
Project description:Marfan syndrome is an extracellular matrix disorder with cardinal manifestations in the eye, skeleton and cardiovascular systems associated with defects in the gene encoding fibrillin (FBN1) at 15q21.1 (ref. 1). A second type of the disorder (Marfan syndrome type 2; OMIM 154705) is associated with a second locus, MFS2, at 3p25-p24.2 in a large French family (family MS1). Identification of a 3p24.1 chromosomal breakpoint disrupting the gene encoding TGF-beta receptor 2 (TGFBR2) in a Japanese individual with Marfan syndrome led us to consider TGFBR2 as the gene underlying association with Marfan syndrome at the MSF2 locus. The mutation 1524G-->A in TGFBR2 (causing the synonymous amino acid substitution Q508Q) resulted in abnormal splicing and segregated with MFS2 in family MS1. We identified three other missense mutations in four unrelated probands, which led to loss of function of TGF-beta signaling activity on extracellular matrix formation. These results show that heterozygous mutations in TGFBR2, a putative tumor-suppressor gene implicated in several malignancies, are also associated with inherited connective-tissue disorders.
| S-EPMC2230615 | biostudies-literature
Project description:Based on the observation of reduced stature in relatives of patients with acromesomelic dysplasia, Maroteaux type (AMDM), caused by homozygous or compound heterozygous mutations in natriuretic peptide receptor-B gene (NPR2), it has been suggested that heterozygous mutations in this gene could be responsible for the growth impairment observed in some cases of idiopathic short stature (ISS). We enrolled 192 unrelated patients with short stature and 192 controls of normal height and identified seven heterozygous NPR2 missense or splice site mutations all in the short stature patients, including one de novo splice site variant. Three of the six inherited variants segregated with short stature in the family. Nine additional rare nonsynonymous NPR2 variants were found in three additional cohorts. Functional studies identified eight loss-of-function mutations in short individuals and one gain-of-function mutation in tall individuals. With these data, we were able to rigorously verify that NPR2 functional haploinsufficiency contributes to short stature. We estimate a prevalence of NPR2 haploinsufficiency of between 0 and 1/26 in people with ISS. We suggest that NPR2 gain of function may be a more common cause of tall stature than previously recognized.
| S-EPMC4382411 | biostudies-literature
Project description:Backgrounds: Recent studies identified heterozygous variants in MYLK3 gene that encodes cardiac myosin light chain kinase (cMLCK) are related to familial dilated cardiomyopathy (DCM) for the first time. Autosomal dominant traits suggest that pathogenesis of DCM could be related to heterozygous MYLK3 loss-of-function variants (haploinsufficiency). We previously generated and examined homozygous Mylk3 knockout mice that lead to heart failure. It had yet to be examined whether heterozygous Mylk3 knockout mice represent a DCM-like phenotype. Methods and Results: Heterozygous knockout (Mylk3 wild/-) mice were examined regarding cardiac function, heart histology and expression of cMLCK protein and mRNA relative to age-matched wild-type controls (Mylk3 wild/wild). At 4 months of age, cardiac contractility in heterozygous knockout mice was reduced with percent fractional shortening of 23.3 ± 1.2% compared to 30.1 ± 1.8% in control (Mylk3 wild/- vs. Mylk3 wild/wild, n = 9 each). In 4-month-old heterozygous knockout hearts, expression of cMLCK mRNA was expectedly reduced by almost half, however, protein expression was reduced by approximately 75% relative to the control wild-type (Mylk3 wild/- vs. Mylk3 wild/wild, n = 9 each). Isolated ventricular cardiomyocytes from heterozygous knockout mice were larger with increase of short-axis length relative to the cardiomyocytes from control mice. However, increase of heart failure markers as well as interstitial fibrosis were not evident in heterozygous knockout mice compared to controls. Conclusion: Heterozygous Mylk3 knockout mice show mild reduction of cardiac contractility by 4 months of age, and proteins reduced by approximately 75% relative to the control wild-type mice. These mice partly resemble human with the heterozygous MYLK3 mutation, but the reduction in cardiac contractility was milder.
| S-EPMC6563786 | biostudies-literature
Project description:AimsWe previously quantified the hypoglycaemia-sparing effect of portal vs peripheral human insulin delivery. The current investigation aimed to determine whether a bioequivalent peripheral vein infusion of a hepatopreferential insulin analog, insulin-406, could similarly protect against hypoglycaemia.Materials and methodsDogs received human insulin infusions into either the hepatic portal vein (PoHI, n = 7) or a peripheral vein (PeHI, n = 7) for 180 minutes at four-fold the basal secretion rate (6.6 pmol/kg/min) in a previous study. Insulin-406 (Pe406, n = 7) was peripherally infused at 6.0 pmol/kg/min, a rate determined to decrease plasma glucose by the same amount as with PoHI infusion during the first 60 minutes. Glucagon was fixed at basal concentrations, mimicking the diminished α-cell response seen in type 1 diabetes.ResultsGlucose dropped quickly with PeHI infusion, reaching 41 ± 3 mg/dL at 60 minutes, but more slowly with PoHI and Pe406 infusion (67 ± 2 and 72 ± 4 mg/dL, respectively; P < 0.01 vs PeHI for both). The hypoglycaemic nadir (c. 40 mg/dL) occurred at 60 minutes with PeHI infusion vs 120 minutes with PoHI and Pe406 infusion. ΔAUCepinephrine during the 180-minute insulin infusion period was two-fold higher with PeHI infusion compared with PoHI and Pe406 infusion. Glucose production (mg/kg/min) was least suppressed with PeHI infusion (Δ = 0.79 ± 0.33) and equally suppressed with PoHI and Pe406 infusion (Δ = 1.16 ± 0.21 and 1.18 ± 0.17, respectively; P = NS). Peak glucose utilization (mg/kg/min) was highest with PeHI infusion (4.94 ± 0.17) and less with PoHI and Pe406 infusion (3.58 ± 0.58 and 3.26 ± 0.08, respectively; P < 0.05 vs Pe for both).ConclusionsPeripheral infusion of hepatopreferential insulin can achieve a metabolic profile that closely mimics portal insulin delivery, which reduces the risk of hypoglycaemia compared with peripheral insulin infusion.
| S-EPMC8132115 | biostudies-literature